Loeys-Dietz syndrome 1

Summary

Loeys-Dietz syndrome 1 (MONDO:0012212) is a disease caused by TGFBR1 (GenCC Definitive), with 3 cohort genes. The dominant Reactome pathway is Loss of Function of TGFBR1 in Cancer (3 cohort genes).

At a glance

• Causal gene: TGFBR1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 150

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Loeys-Dietz syndrome 1
Mondo ID	MONDO:0012212
OMIM	609192
Orphanet	97295
DOID	DOID:0070235
NCIT	C75119
UMLS	C4551955
MedGen	1646567
GARD	0009458
Is cancer (heuristic)	no

Also known as: Furlong syndrome · LDS1 · Loeys-Dietz syndrome 1 · Loeys-Dietz syndrome caused by mutation in TGFBR1 · Loeys-Dietz syndrome type 1 · TGFBR1 Loeys-Dietz syndrome

Data availability: 150 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Loeys-Dietz syndrome › Loeys-Dietz syndrome 1

Related subtypes (5): Loeys-Dietz syndrome 2, aneurysm-osteoarthritis syndrome, Loeys-Dietz syndrome 4, Rienhoff syndrome, Loeys-Dietz syndrome 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

150 retrieved; paginated sample, class counts are floors:

84 uncertain significance, 31 conflicting classifications of pathogenicity, 13 likely pathogenic, 10 pathogenic, 7 pathogenic/likely pathogenic, 2 benign/likely benign, 2 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12520	NM_004612.4(TGFBR1):c.953T>G (p.Met318Arg)	TGFBR1	Pathogenic	no assertion criteria provided
12521	NM_004612.4(TGFBR1):c.1199A>G (p.Asp400Gly)	TGFBR1	Pathogenic	no assertion criteria provided
12522	NM_004612.4(TGFBR1):c.599C>T (p.Thr200Ile)	TGFBR1	Pathogenic	no assertion criteria provided
12523	NM_004612.4(TGFBR1):c.1460G>C (p.Arg487Pro)	TGFBR1	Pathogenic	criteria provided, single submitter
12524	NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)	TGFBR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12525	NM_004612.4(TGFBR1):c.1460G>A (p.Arg487Gln)	TGFBR1	Pathogenic	criteria provided, multiple submitters, no conflicts
12526	NM_004612.4(TGFBR1):c.1459C>T (p.Arg487Trp)	TGFBR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213882	NM_004612.4(TGFBR1):c.934G>A (p.Gly312Ser)	TGFBR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213884	NM_004612.4(TGFBR1):c.797A>G (p.Asp266Gly)	TGFBR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3773662	NM_004612.4(TGFBR1):c.90_91delinsT (p.Ala31fs)	TGFBR1	Pathogenic	criteria provided, single submitter
3899364	NM_004612.4(TGFBR1):c.688G>A (p.Ala230Thr)	TGFBR1	Pathogenic	criteria provided, single submitter
3901184	NM_004612.4(TGFBR1):c.91del (p.Ala31fs)	TGFBR1	Pathogenic	criteria provided, single submitter
4682101	T274S	TGFBR1	Pathogenic	no assertion criteria provided
4682102	M253I	TGFBR1	Pathogenic	no assertion criteria provided
488621	NM_004612.4(TGFBR1):c.640G>A (p.Gly214Ser)	TGFBR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265447	NM_003242.6(TGFBR2):c.1336G>A (p.Asp446Asn)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694685	NM_003242.6(TGFBR2):c.1512G>A (p.Trp504Ter)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709170	NM_005901.6(SMAD2):c.507_508del (p.Arg169fs)	SMAD2	Likely pathogenic	criteria provided, single submitter
1022363	NM_004612.4(TGFBR1):c.791CAG[1] (p.Ala265del)	TGFBR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1034099	NM_004612.4(TGFBR1):c.829T>A (p.Trp277Arg)	TGFBR1	Likely pathogenic	criteria provided, single submitter
1067739	NM_004612.4(TGFBR1):c.943C>T (p.His315Tyr)	TGFBR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320270	NM_004612.4(TGFBR1):c.640G>C (p.Gly214Arg)	TGFBR1	Likely pathogenic	criteria provided, single submitter
1332769	NM_004612.4(TGFBR1):c.1198G>A (p.Asp400Asn)	TGFBR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805069	NM_004612.4(TGFBR1):c.1468A>G (p.Lys490Glu)	TGFBR1	Likely pathogenic	criteria provided, single submitter
3075667	NM_004612.4(TGFBR1):c.650G>A (p.Gly217Glu)	TGFBR1	Likely pathogenic	criteria provided, single submitter
3806422	NM_004612.4(TGFBR1):c.673C>G (p.Arg225Gly)	TGFBR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4530633	NM_004612.4(TGFBR1):c.1058dup (p.Leu354fs)	TGFBR1	Likely pathogenic	criteria provided, single submitter
520505	NM_004612.4(TGFBR1):c.1061T>C (p.Leu354Pro)	TGFBR1	Likely pathogenic	criteria provided, single submitter
800489	NM_004612.4(TGFBR1):c.735G>C (p.Glu245Asp)	TGFBR1	Likely pathogenic	no assertion criteria provided
992362	NM_004612.4(TGFBR1):c.827T>C (p.Leu276Pro)	TGFBR1	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TGFBR1	Definitive	Autosomal dominant	Loeys-Dietz syndrome 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR2	Orphanet:144	Lynch syndrome
TGFBR2	Orphanet:284973	Marfan syndrome type 2
TGFBR2	Orphanet:60030	Loeys-Dietz syndrome
TGFBR2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR2	Orphanet:99977	Squamous cell carcinoma of the esophagus
SMAD2	Orphanet:60030	Loeys-Dietz syndrome
SMAD2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	gencc,clinvar
TGFBR2	HGNC:11773	ENSG00000163513	P37173	TGF-beta receptor type-2	clinvar
SMAD2	HGNC:6768	ENSG00000175387	Q15796	SMAD family member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
TGFBR2	TGF-beta receptor type-2	Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
SMAD2	SMAD family member 2	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	2	18.5×	0.008
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
TGFBR2	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
SMAD2	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibia	2
saphenous vein	1
visceral pleura	1
parietal pleura	1
pericardium	1
calcaneal tendon	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
TGFBR2	289	ubiquitous	marker	pericardium, tibia, parietal pleura
SMAD2	299	ubiquitous	marker	calcaneal tendon, sperm, male germ cell

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGFBR2	5,777
SMAD2	5,751
TGFBR1	4,828

Intra-cohort edges

A	B	Sources
SMAD2	TGFBR1	string_interaction
SMAD2	TGFBR2	string_interaction
TGFBR1	TGFBR2	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBR1	P36897	44
TGFBR2	P37173	22
SMAD2	Q15796	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Loss of Function of TGFBR1 in Cancer	3	2284.0×	7e-10	TGFBR1, TGFBR2, SMAD2
Loss of Function of SMAD2/3 in Cancer	3	1903.3×	7e-10	TGFBR1, TGFBR2, SMAD2
Signaling by TGF-beta Receptor Complex in Cancer	3	1903.3×	7e-10	TGFBR1, TGFBR2, SMAD2
SMAD2/3 Phosphorylation Motif Mutants in Cancer	3	1903.3×	7e-10	TGFBR1, TGFBR2, SMAD2
TGFBR1 KD Mutants in Cancer	3	1903.3×	7e-10	TGFBR1, TGFBR2, SMAD2
Downregulation of TGF-beta receptor signaling	3	407.9×	1e-07	TGFBR1, TGFBR2, SMAD2
TGF-beta receptor signaling activates SMADs	3	326.3×	2e-07	TGFBR1, TGFBR2, SMAD2
Loss of Function of TGFBR2 in Cancer	2	2537.8×	6e-07	TGFBR1, TGFBR2
TGFBR2 Kinase Domain Mutants in Cancer	2	2537.8×	6e-07	TGFBR1, TGFBR2
Signaling by TGF-beta Receptor Complex	3	200.3×	6e-07	TGFBR1, TGFBR2, SMAD2
TGFBR1 LBD Mutants in Cancer	2	1903.3×	1e-06	TGFBR1, TGFBR2
Deubiquitination	3	124.1×	2e-06	TGFBR1, TGFBR2, SMAD2
Signaling by TGFB family members	3	115.3×	2e-06	TGFBR1, TGFBR2, SMAD2
TGFBR3 regulates TGF-beta signaling	2	951.7×	4e-06	TGFBR1, TGFBR2
Diseases of signal transduction by growth factor receptors and second messengers	3	56.8×	2e-05	TGFBR1, TGFBR2, SMAD2
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)	2	447.8×	2e-05	TGFBR1, TGFBR2
Signaling by TGFBR3	2	245.6×	6e-05	TGFBR1, TGFBR2
Post-translational protein modification	3	19.2×	3e-04	TGFBR1, TGFBR2, SMAD2
UCH proteinases	2	82.8×	4e-04	TGFBR1, TGFBR2
Disease	3	13.1×	1e-03	TGFBR1, TGFBR2, SMAD2
TGFBR2 MSI Frameshift Mutants in Cancer	1	1903.3×	0.001	TGFBR2
Metabolism of proteins	3	12.4×	0.001	TGFBR1, TGFBR2, SMAD2
Loss of Function of SMAD4 in Cancer	1	1268.9×	0.001	SMAD2
SMAD4 MH2 Domain Mutants in Cancer	1	1268.9×	0.001	SMAD2
SMAD2/3 MH2 Domain Mutants in Cancer	1	1268.9×	0.001	SMAD2
Signal Transduction	3	10.2×	0.002	TGFBR1, TGFBR2, SMAD2
Ub-specific processing proteases	2	35.4×	0.002	TGFBR1, SMAD2
Formation of axial mesoderm	1	271.9×	0.006	SMAD2
Signaling by Activin	1	253.8×	0.006	SMAD2
Formation of definitive endoderm	1	237.9×	0.006	SMAD2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to cholesterol	3	1685.2×	2e-08	TGFBR1, TGFBR2, SMAD2
activin receptor signaling pathway	3	887.0×	9e-08	TGFBR1, TGFBR2, SMAD2
embryonic cranial skeleton morphogenesis	3	581.1×	2e-07	TGFBR1, TGFBR2, SMAD2
positive regulation of epithelial to mesenchymal transition	3	318.0×	1e-06	TGFBR1, TGFBR2, SMAD2
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	2	2808.7×	4e-06	TGFBR1, TGFBR2
transforming growth factor beta receptor signaling pathway	3	159.0×	6e-06	TGFBR1, TGFBR2, SMAD2
trophoblast cell migration	2	1605.0×	9e-06	TGFBR1, SMAD2
secondary palate development	2	802.5×	4e-05	TGFBR2, SMAD2
in utero embryonic development	3	72.0×	4e-05	TGFBR1, TGFBR2, SMAD2
SMAD protein signal transduction	2	488.5×	8e-05	TGFBR2, SMAD2
gastrulation	2	468.1×	8e-05	TGFBR2, SMAD2
artery morphogenesis	2	449.4×	8e-05	TGFBR1, TGFBR2
aortic valve morphogenesis	2	288.1×	2e-04	TGFBR2, SMAD2
ventricular septum morphogenesis	2	288.1×	2e-04	TGFBR1, TGFBR2
positive regulation of SMAD protein signal transduction	2	255.3×	2e-04	TGFBR1, TGFBR2
lens development in camera-type eye	2	249.7×	2e-04	TGFBR1, TGFBR2
cellular response to growth factor stimulus	2	212.0×	2e-04	TGFBR1, TGFBR2
epithelial to mesenchymal transition	2	208.1×	2e-04	TGFBR1, TGFBR2
roof of mouth development	2	165.2×	4e-04	TGFBR1, TGFBR2
post-embryonic development	2	137.0×	5e-04	TGFBR1, SMAD2
anterior/posterior pattern specification	2	120.8×	6e-04	TGFBR1, SMAD2
positive regulation of tolerance induction to self antigen	1	5617.3×	0.001	TGFBR2
positive regulation of B cell tolerance induction	1	5617.3×	0.001	TGFBR2
extracellular structure organization	1	5617.3×	0.001	TGFBR1
inferior endocardial cushion morphogenesis	1	5617.3×	0.001	TGFBR2
bronchus morphogenesis	1	2808.7×	0.002	TGFBR2
mammary gland morphogenesis	1	2808.7×	0.002	TGFBR2
epicardium morphogenesis	1	2808.7×	0.002	TGFBR1
regulation of gene expression	2	55.6×	0.002	TGFBR1, TGFBR2
zygotic specification of dorsal/ventral axis	1	1872.4×	0.002	SMAD2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TGFBR1	MOMELOTINIB
TGFBR2	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBR1	28	4
TGFBR2	22	4
SMAD2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1, TGFBR2
NINTEDANIB	4	TGFBR1
DASATINIB	4	TGFBR1, TGFBR2
CRIZOTINIB	4	TGFBR1
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	TGFBR2
SORAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1, TGFBR2
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	TGFBR1, TGFBR2
ALVOCIDIB	3	TGFBR2
GALUNISERTIB	2	TGFBR1, TGFBR2
OSI-632	2	TGFBR1
OSI-027	2	TGFBR1
VACTOSERTIB	2	TGFBR1
BMS-690514	2	TGFBR1
DANUSERTIB	2	TGFBR1, TGFBR2
R-406	2	TGFBR1, TGFBR2
AT-9283	2	TGFBR1, TGFBR2
ZILURGISERTIB	2	TGFBR1
TOZASERTIB	2	TGFBR1
KER-047	2	TGFBR1
SCH-900776	2	TGFBR2
TG100-801	2	TGFBR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
TGFBR2	188	Binding:188
SMAD2	20	Binding:20

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
TGFBR2	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TGFBR1	541
TGFBR2	188

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1, TGFBR2
NINTEDANIB	4	TGFBR1
DASATINIB	4	TGFBR1, TGFBR2
CRIZOTINIB	4	TGFBR1
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	TGFBR2
SORAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1, TGFBR2
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	TGFBR1, TGFBR2
ALVOCIDIB	3	TGFBR2
GALUNISERTIB	2	TGFBR1, TGFBR2
OSI-632	2	TGFBR1
OSI-027	2	TGFBR1
VACTOSERTIB	2	TGFBR1
BMS-690514	2	TGFBR1
DANUSERTIB	2	TGFBR1, TGFBR2
R-406	2	TGFBR1, TGFBR2
AT-9283	2	TGFBR1, TGFBR2
ZILURGISERTIB	2	TGFBR1
TOZASERTIB	2	TGFBR1
KER-047	2	TGFBR1
SCH-900776	2	TGFBR2
TG100-801	2	TGFBR2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TGFBR1, TGFBR2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SMAD2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SMAD2	20	TGFBR1

Clinical trials & evidence

Clinical trials

Clinical trials: 0.